Hexokinase II protein content is a determinant of exercise endurance capacity in the mouse

Fueger, Patrick T.; Shearer, Jane; Krueger, Tess M.; Posey, Kelly A.; Bracy, Deanna P.; Heikkinen, Sami; Laakso, Markku; Rottman, Jeffrey N.; Wasserman, David H.

doi:10.1113/jphysiol.2005.085043

Cited by 53 publications

(46 citation statements)

References 43 publications

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“…Interestingly, the premature fatigue was closely correlated with exercise-stimulated MGU, and thus endurance capacity and MGU may be linked in the mouse. We previously reported that skeletal muscle HK II content, exercise-stimulated MGU, and exercise endurance capacity are closely correlated (6). Here we show that high-fat feeding, which impairs exercisestimulated MGU by 50%, is associated with a 40% reduction in endurance time in the mouse.…”

Section: Discussionmentioning

confidence: 56%

“…Procedures were approved by the Vanderbilt University Animal Care and Use Committee. Male Ukko1 (a mixture of BALB/c and DBA/2 strains) mice containing a partial deletion to the HK II gene (HK ϩ/Ϫ ) that results in a 50% reduction in HK II activity in heart, skeletal muscle, and adipose tissue, but does not change HK I activity (5), were backcrossed onto the C57BL/6J background for at least five generations (6). At 3 weeks of age, littermates were separated by sex and maintained in microisolator cages.…”

Section: Methodsmentioning

confidence: 99%

“…Endurance capacity. In separate groups of animals, exercise endurance was measured as previously described (6). Briefly, mice were placed in an enclosed treadmill (Columbus Instruments) and allowed to acclimate to their surroundings for 45 min.…”

Section: Hyperinsulinemic-euglycemic Clamp and Saline Control Experimmentioning

confidence: 99%

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Phosphorylation Barriers to Skeletal and Cardiac Muscle Glucose Uptakes in High-Fat–Fed Mice

et al. 2007

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OBJECTIVE-Muscle glucose uptake (MGU) is regulated by glucose delivery to, transport into, and phosphorylation within muscle. The aim of this study was to determine the role of limitations in glucose phosphorylation in the control of MGU during either physiological insulin stimulation (4 mU ⅐ kg Ϫ1 ⅐ min Ϫ1 ) or exercise with chow or high-fat feeding. RESEARCH DESIGN AND METHODS-C57BL/6J mice with (HKϩ/Ϫ ) and without (WT) a 50% hexokinase (HK) II deletion were fed chow or high-fat diets and studied at 4 months of age during a 120-min insulin clamp or 30 min of treadmill exercise (n ϭ 8 -10 mice/group). 2-deoxy[ 3 H]glucose was used to measure R g , an index of MGU.RESULTS-Body weight and fasting arterial glucose were increased by high-fat feeding and partial HK II knockout (HK ϩ/Ϫ ). Both high-fat feeding and partial HK II knockout independently created fasting hyperinsulinemia, a response that was increased synergistically with combined high-fat feeding and HK II knockout. Whole-body insulin action was suppressed by ϳ25% with either high-fat feeding or partial HK II knockout alone but by Ͼ50% when the two were combined. Insulin-stimulated R g was modestly impaired by high-fat feeding and partial HK II knockout independently (ϳ15-20%) but markedly reduced by the two together (ϳ40 -50%). Exercise-stimulated R g was reduced by ϳ50% with high-fat feeding and partial HK II knockout alone and was not attenuated further by combining the two.CONCLUSIONS-In summary, impairments in whole-body metabolism and MGU due to high-fat feeding and partial HK II knockout combined during insulin stimulation are additive. In contrast, combining high-fat feeding and partial HK II knockout during exercise causes no greater impairment in MGU than the two manipulations independently. This suggests that MGU is impaired during exercise by high-fat feeding due to, in large part, a limitation in glucose phosphorylation. Together, these studies show that the high-fat-fed mouse is characterized by defects at multiple steps of the MGU system that are precipitated by different physiological conditions. Diabetes 56:2476-2484, 2007 T he importance of limitations in muscle glucose phosphorylation capacity in insulin resistance is a point of contention. In rodent muscle, glucose phosphorylation to glucose-6-phosphate is catalyzed primarily by the hexokinase (HK) II isozyme. HK II content may be normal (1) or reduced (2) in insulinresistant states, depending on the muscle fiber type composition. Regardless, glucose phosphorylation capacity is affected due to allosteric inhibition of HK II by acyl-CoA and glucose-6-phosphate or compartmentation of HK II, its allosteric regulators, and its substrates (i.e., glucose and ATP). Insulin stimulation and exercise can be used to expose functional deficits in glucose phosphorylation capacity that may otherwise be undetectable (3). Indeed, we previously used such a strategy in conscious mice overexpressing HK II to provide evidence that glucose phosphorylation is, in fact, impaired by high-fat feeding (4). Th...

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Section: Discussionmentioning

confidence: 56%

Section: Methodsmentioning

confidence: 99%

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Phosphorylation Barriers to Skeletal and Cardiac Muscle Glucose Uptakes in High-Fat–Fed Mice

et al. 2007

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“…Skeletal muscle glucose uptake during muscle contractions is dependent on hexokinase II and GLUT4 (29,30), but the expression of these proteins was not altered in β1β2M-KO mice (Fig. 4G).…”

Section: Ampk β1β2m-ko Mice Have Reduced Skeletal Muscle Glucose Uptakementioning

confidence: 99%

AMP-activated protein kinase (AMPK) β1β2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise

O’Neill

Maarbjerg

Crane

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

371

388

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AMP-activated protein kinase (AMPK) β1 or β2 subunits are required for assembling of AMPK heterotrimers and are important for regulating enzyme activity and cellular localization. In skeletal muscle, α2β2γ3-containing heterotrimers predominate. However, compensatory up-regulation and redundancy of AMPK subunits in wholebody AMPK α2, β2, and γ3 null mice has made it difficult to determine the physiological importance of AMPK in regulating muscle metabolism, because these models have normal mitochondrial content, contraction-stimulated glucose uptake, and insulin sensitivity. In the current study, we generated mice lacking both AMPK β1 and β2 isoforms in skeletal muscle (β1β2M-KO). β1β2M-KO mice are physically inactive and have a drastically impaired capacity for treadmill running that is associated with reductions in skeletal muscle mitochondrial content but not a fiber-type switch. Interestingly, young β1β2M-KO mice fed a control chow diet are not obese or insulin resistant but do have impaired contraction-stimulated glucose uptake. These data demonstrate an obligatory role for skeletal muscle AMPK in maintaining mitochondrial capacity and contraction-stimulated glucose uptake, findings that were not apparent in mice with single mutations or deletions in muscle α, β, or γ subunits.is an evolutionarily conserved stress-sensing kinase that controls energy metabolism and appetite by responding to nutrients and hormones (1). The regulation of AMPK activity depends on AMP and ADP regulated phosphorylation of the α catalytic subunit at T172 by the upstream kinases LKB1 and Ca 2+ /CaM-dependent protein kinase kinase (CaMKKβ; refs. 2 and 3). AMPK exists as a heterotrimer, consisting of an α catalytic subunit (α1, α2), a scaffolding β subunit (β1, β2) and a nucleotide-binding γ subunit (γ1, γ2, γ3) (1). The C-terminal of the β subunit contains a highly conserved α and γ subunit-binding sequence (SBS) that is required for the formation of a stable, active AMPK αβγ complex (4). We recently reported on the physiological effects of germline deletion of β1 (5) and β2 (6) isoforms in mice. We showed that β1 null mice have reduced AMPK α-subunit expression and activity in liver, adipose tissue and the hypothalamus (5). In contrast, AMPK β2 null mice have reduced AMPK activity in skeletal muscle, are aminoimidazole carboxamide ribonucleotide (AICAR) insensitive and have reduced exercise tolerance despite a greater than 50% increase in muscle β1 protein expression (6). The phenotype of β2 null mice was similar to that of mice lacking α2 (7) or γ3 (8) subunits or muscle-specific overexpression of an α2 kinase dead (KD) mutation (9, 10).During exercise, AMPK is activated in an intensity-dependent manner (for review, see ref. 11). Mice with reduced AMPK in muscle are exercise intolerant, an effect shown not to be due to cardiac impairments in AMPK (12-14). However, the cause for this reduction in exercise capacity remains largely unknown, because mitochondrial content and glucose uptake are not altered (6,7,10,12,(15)(16)(17) or onl...

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“…In many tissues including skeletal muscle, GLUT1 and GLUT4 predominate, with GLUT4 translocation to the plasma membrane and t tubules considered rate-limiting for the uptake of glucose in response to stimuli such as muscle contraction and insulin; however, it should be noted that under some situations, glucose phosphorylation by hexokinase also appears to be important (154,155). Importantly, during exercise and/or skeletal muscle contraction, glucose uptake is increased, an effect which is independent of the proximal part of the insulin signaling pathway (for review, see Ref.…”

Section: A Glucose Uptakementioning

confidence: 99%

AMPK in Health and Disease

Steinberg¹,

Kemp²

2009

Physiological Reviews

1,459

1,419

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The function and survival of all organisms is dependent on the dynamic control of energy metabolism, when energy demand is matched to energy supply. The AMP-activated protein kinase (AMPK) αβγ heterotrimer has emerged as an important integrator of signals that control energy balance through the regulation of multiple biochemical pathways in all eukaryotes. In this review, we begin with the discovery of the AMPK family and discuss the recent structural studies that have revealed the molecular basis for AMP binding to the enzyme's γ subunit. AMPK's regulation involves autoinhibitory features and phosphorylation of both the catalytic α subunit and the β-targeting subunit. We review the role of AMPK at the cellular level through examination of its many substrates and discuss how it controls cellular energy balance. We look at how AMPK integrates stress responses such as exercise as well as nutrient and hormonal signals to control food intake, energy expenditure, and substrate utilization at the whole body level. Lastly, we review the possible role of AMPK in multiple common diseases and the role of the new age of drugs targeting AMPK signaling.

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Hexokinase II protein content is a determinant of exercise endurance capacity in the mouse

Cited by 53 publications

References 43 publications

Phosphorylation Barriers to Skeletal and Cardiac Muscle Glucose Uptakes in High-Fat–Fed Mice

Phosphorylation Barriers to Skeletal and Cardiac Muscle Glucose Uptakes in High-Fat–Fed Mice

AMP-activated protein kinase (AMPK) β1β2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise

AMPK in Health and Disease

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